Rates and risk factors of hypertension in adolescents and adults with sickle cell anaemia in Tanzania: 10 years' experience.

Data on the magnitude and risk factors for hypertension in sickle cell anaemia (SCA) are limited. A retrospective analysis of individuals with SCA aged ≥15 years enrolled from 2004-2014 at Muhimbili National Hospital, Tanzania was conducted to determine the prevalence, incidence and risk factors for hypertension. A total of 1013 individuals with SCA were analysed, of whom 571(56%) were females. The median age [interquartile range] was 17 [15-22] years. Four hundred and forty-one (44%) of the patients had relative hypertension [systolic blood pressure (SBP) 120-139 mmHg or diastolic blood pressure (DBP) 70-89 mmHg], and 79 (8%) had hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg). The incidence of hypertension was 64/1000 person years of observation and the 5-year survival rate was 0·71 [95% confidence interval (CI): 0·67-0·75]. In multivariate analysis, age>18 years, Hazard ratio (HR) 1·50 (95% CI: 1·03-2·18); pulse pressure, HR 0·64 (95% CI: 0·42 to 0·98); pulse rate, 1·02 (95% CI: 1·01-1·03); body mass index (BMI), HR 1·08 (95% CI: 1·03-1·13); blood transfusion, HR 2·50 (95% CI: 1·01-6·21) and haemoglobin, HR 1·12 (95% CI: 1·05-1·33) were independently associated with hypertension. In conclusion, despite the younger age, hypertension in this population was higher than that reported in others studies. Age, BMI, pulse pressure and haemoglobin were independently associated with hypertension in SCA.

Genetic association of fetal-hemoglobin levels in individuals with sickle cell disease in Tanzania maps to conserved regulatory elements within the MYB core enhancer.

BACKGROUND: Common genetic variants residing near upstream regulatory elements for MYB, the gene encoding transcription factor cMYB, promote the persistence of fetal hemoglobin (HbF) into adulthood. While they have no consequences in healthy individuals, high HbF levels have major clinical benefits in patients with sickle cell disease (SCD) or ß thalassemia. Here, we present our detailed investigation of HBS1L-MYB intergenic polymorphism block 2 (HMIP-2), the central component of the complex quantitative-trait locus upstream of MYB, in 1,022 individuals with SCD in Tanzania. METHODS: We have looked at 1022 individuals with HbSS or HbS/ß(0) in Tanzania. In order to achieve a detailed analysis of HMIP-2, we performed targeted genotyping for a total of 10 SNPs and extracted additional 528 SNPs information from a genome wide scan involving the same population. Using MACH, we utilized the existing YRI data from 1000 genomes to impute 54 SNPs situated within HIMP-2. RESULTS: Seven HbF-increasing, low-frequency variants (ß > 0.3, p < 10(-5), f ≤ 0.05) were located in two partially-independent sub-loci, HMIP-2A and HMIP-2B. The spectrum of haplotypes carrying such alleles was diverse when compared to European and West African reference populations: we detected one such haplotype at sub-locus HMIP-2A, two at HMIP-2B, and a fourth including high-HbF alleles at both sub-loci ('Eurasian' haplotype clade). In the region of HMIP-2A a putative functional variant (a 3-bp indel) has been described previously, but no such candidate causative variant exists at HMIP-2B. Extending our dataset through imputation with 1000 Genomes, whole-genome-sequence data, we have mapped peak association at HMIP-2B to an 11-kb region around rs9494145 and rs9483788, flanked by two conserved regulatory elements for MYB. CONCLUSIONS: Studies in populations from the African continent provide distinct opportunities for mapping disease-modifying genetic loci, especially for conditions that are highly prevalent there, such as SCD. Population-genetic characteristics of our cohort, such as ethnic diversity and the predominance of shorter, African-type haplotypes, can add to the power of such studies.

Prevalence of Urinary Tract Infections and Antibiogram of Bacteria Isolated From Children With Sickle Cell Disease in Tanzania.

Introduction Individuals with sickle cell disease (SCD) are particularly vulnerable to urinary tract infections (UTIs) due to immunological deficits and renal abnormalities associated with the disorder. These infections can exacerbate underlying health issues and lead to severe complications if not managed promptly and effectively. Due to the heightened risk and potential consequences of UTIs in this population, this study aimed to determine their prevalence and explore the resistance patterns of causative pathogens among children attending the SCD Clinic at Muhimbili National Hospital (MNH), Dar es Salaam, Tanzania. Focusing on this demographic group, we sought to provide targeted insights to inform better clinical protocols and intervention strategies in regions heavily affected by SCD. Materials and methods This prospective cross-sectional study was conducted at the MNH, Dar es Salaam, Tanzania, with an enrollment over two months from 19th March to 21st May 2015. We diagnosed UTIs in children with SCD using dipstick and culture methods. Antibiotic susceptibility was assessed using the Kirby-Bauer disc diffusion method, evaluating resistance patterns to antibiotics such as ampicillin, cloxacillin, erythromycin, chloramphenicol, ceftriaxone, and trimethoprim-sulfamethoxazole. The diagnostic accuracy of the dipstick and culture methods was validated to ensure reliability in detecting UTIs. Statistical analysis was conducted using Statistical Product and Service Solutions (SPSS) software (Released 2019; IBM Corp., Armonk, New York, United States). Results Among the 250 children, 56 (22.4%) were UTI-positive according to the culture method and 62 (24.8%) were UTI-positive according to the dipstick test. Girls were more likely to be UTI-positive than boys (29.1% and 13.6%, respectively; p-value = 0.011). Escherichia coli was the most common uropathogen, followed by Klebsiella, Staphylococcus, Proteus, and Pseudomonas (44.2%, 26.9%, 21.2%, 3.8%, and 1.9%, respectively). All isolates were resistant to ampiclox. Resistance rates to ampicillin, erythromycin, cotrimoxazole, chloramphenicol, and ceftriaxone were 94.2%, 76.9%, 59.6%, 46.2%, and 21.2%, respectively. Conclusion This study indicated that dipsticks diagnosed more UTIs. The prevalence was higher in girls than in boys. Escherichia coli was the most commonly isolated antibiotic-resistant organism. High resistance levels were observed against the combination of ampicillin and cloxacillin. However, the isolates were less resistant to ceftriaxone. These results call for increased surveillance of resistant uropathogens in the pediatric population with SCD.

Genetics of fetal hemoglobin in Tanzanian and British patients with sickle cell anemia.

Fetal hemoglobin (HbF, α(2)γ(2)) is a major contributor to the remarkable phenotypic heterogeneity of sickle cell anemia (SCA). Genetic variation at 3 principal loci (HBB cluster on chromosome 11p, HBS1L-MYB region on chromosome 6q, and BCL11A on chromosome 2p) have been shown to influence HbF levels and disease severity in ß-thalassemia and SCA. Previous studies in SCA, however, have been restricted to populations from the African diaspora, which include multiple genealogies. We have investigated the influence of these 3 loci on HbF levels in sickle cell patients from Tanzania and in a small group of African British sickle patients. All 3 loci have a significant impact on the trait in both patient groups. The results suggest the presence of HBS1L-MYB variants affecting HbF in patients who are not tracked well by European-derived markers, such as rs9399137. Additional loci may be identified through independent genome-wide association studies in African populations.

Nutritional status, hospitalization and mortality among patients with sickle cell anemia in Tanzania.

BACKGROUND: Reduced growth is common in children with sickle cell anemia, but few data exist on associations with long-term clinical course. Our objective was to determine the prevalence of malnutrition at enrollment into a hospital-based cohort and whether poor nutritional status predicted morbidity and mortality within an urban cohort of Tanzanian sickle cell anemia patients. DESIGN AND METHODS: Anthropometry was conducted at enrollment into the sickle cell anemia cohort (n=1,618; ages 0.5-48 years) and in controls who attended screening (siblings, walk-ins and referrals) but who were found not to have sickle cell anemia (n=717; ages 0.5-64 years). Prospective surveillance recorded hospitalization at Muhimbili National Hospital and mortality between March 2004 and September 2009. RESULTS: Sickle cell anemia was associated with stunting (OR=1.92, P<0.001, 36.2%) and wasting (OR=1.66, P=0.002, 18.4%). The greatest growth deficits were observed in adolescents and in boys. Independent of age and sex, lower hemoglobin concentration was associated with increased odds of malnutrition in sickle cell patients. Of the 1,041 sickle cell anemia patients with a body mass index z-score at enrollment, 92% were followed up until September 2009 (n=908) or death (n=50). Body mass index and weight-for-age z-score predicted hospitalization (hazard ratio [HZR]=0.90, P=0.04 and HZR=0.88, P=0.02) but height-for-age z-score did not (HZR=0.93, NS). The mortality rate of 2.5 per 100 person-years was not associated with any of the anthropometric measures. CONCLUSIONS: In this non-birth-cohort of sickle cell anemia with significant associated undernutrition, wasting predicted an increased risk of hospital admission. Targeted nutritional interventions should prioritize treatment and prevention of wasting.

A ten year review of the sickle cell program in Muhimbili National Hospital, Tanzania.

BACKGROUND: Africa has the highest burden of Sickle cell disease (SCD) but there are few large, systematic studies providing reliable descriptions of the disease spectrum. Tanzania, with 11,000 SCD births annually, established the Muhimbili Sickle Cell program aiming to improve understanding of SCD in Africa. We report the profile of SCD seen in the first 10 years at Muhimbili National Hospital (MNH). METHODS: Individuals seen at MNH known or suspected to have SCD were enrolled at clinic and laboratory testing for SCD, haematological and biochemical analyses done. Ethnicity was self-reported. Clinical and laboratory features of SCD were documented. Comparison was made with non-SCD population as well as within 3 different age groups (< 5, 5-17 and ≥ 18 years) within the SCD population. RESULTS: From 2004 to 2013, 6397 individuals, 3751 (58.6%) SCD patients, were enrolled, the majority (47.4%) in age group 5-17 years. There was variation in the geographical distribution of SCD. Individuals with SCD compared to non-SCD, had significantly lower blood pressure and peripheral oxygen saturation (SpO2). SCD patients had higher prevalence of severe anemia, jaundice and desaturation (SpO2 < 95%) as well as higher levels of reticulocytes, white blood cells, platelets and fetal hemoglobin. The main causes of hospitalization for SCD within a 12-month period preceding enrolment were pain (adults), and fever and severe anemia (children). When clinical and laboratory features were compared in SCD within 3 age groups, there was a progressive decrease in the prevalence of splenic enlargement and an increase in prevalence of jaundice. Furthermore, there were significant differences with monotonic trends across age groups in SpO2, hematological and biochemical parameters. CONCLUSION: This report confirms that the wide spectrum of clinical expression of SCD observed elsewhere is also present in Tanzania, with non-uniform geographical distribution across the country. Age-specific analysis is consistent with different disease-patterns across the lifespan.

Genome wide association study of fetal hemoglobin in sickle cell anemia in Tanzania.

BACKGROUND: Fetal hemoglobin (HbF) is an important modulator of sickle cell disease (SCD). HbF has previously been shown to be affected by variants at three loci on chromosomes 2, 6 and 11, but it is likely that additional loci remain to be discovered. METHODS AND FINDINGS: We conducted a genome-wide association study (GWAS) in 1,213 SCA (HbSS/HbSß0) patients in Tanzania. Genotyping was done with Illumina Omni2.5 array and imputation using 1000 Genomes Phase I release data. Association with HbF was analysed using a linear mixed model to control for complex population structure within our study. We successfully replicated known associations for HbF near BCL11A and the HBS1L-MYB intergenic polymorphisms (HMIP), including multiple independent effects near BCL11A, consistent with previous reports. We observed eight additional associations with P<10(-6). These associations could not be replicated in a SCA population in the UK. CONCLUSIONS: This is the largest GWAS study in SCA in Africa. We have confirmed known associations and identified new genetic associations with HbF that require further replication in SCA populations in Africa.

Sickle cell anemia: iron availability and nocturnal oximetry.

STUDY OBJECTIVE: To test the hypothesis that low iron availability, measured as transferrin saturation, is associated with low nocturnal hemoglobin oxygen saturation (SpO(2)) in children with homozygous sickle cell anemia (SCA; hemoglobin SS). METHODS: This was a cross-sectional study of Tanzanian children with SCA who were not receiving regular blood transfusions. Thirty-two children (16 boys) with SCA (mean age 8.0, range 3.6-15.3 years) underwent motion-resistant nocturnal oximetry (Masimo Radical) and had steady state serum transferrin saturation and hematological indices assessed. RESULTS: Higher transferrin saturation, adjusted for age and α-thalassemia deletion, was associated with lower nocturnal mean SpO(2) (p = 0.013, r(2) = 0.41), number of SpO(2) dips/h > 3% from baseline (p = 0.008, r(2) = 0.19) and with min/h with SpO(2) < 90% (p = 0.026 r(2) = 0.16). Transferrin saturation < 16% (indicative of iron deficiency) was associated with a 2.2% higher nocturnal mean SpO(2). CONCLUSIONS: Contrary to our hypothesis, higher iron availability, assessed by transferrin saturation, is associated with nocturnal chronic and intermittent hemoglobin oxygen desaturation in SCA. Whether these associations are causal and are driven by hypoxia-inducible factor and hepcidin-mediated upregulation of demand for iron warrants further investigation.

Mortality in sickle cell anemia in Africa: a prospective cohort study in Tanzania.

BACKGROUND: The World Health Organization has declared Sickle Cell Anemia (SCA) a public health priority. There are 300,000 births/year, over 75% in Africa, with estimates suggesting that 6 million Africans will be living with SCA if average survival reaches half the African norm. Countries such as United States of America and United Kingdom have reduced SCA mortality from 3 to 0.13 per 100 person years of observation (PYO), with interventions such as newborn screening, prevention of infections and comprehensive care, but implementation of interventions in African countries has been hindered by lack of locally appropriate information. The objective of this study was to determine the incidence and factors associated with death from SCA in Dar-es-Salaam. METHODS AND FINDINGS: A hospital-based cohort study was conducted, with prospective surveillance of 1,725 SCA patients recruited from 2004 to 2009, with 209 (12%) lost to follow up, while 86 died. The mortality rate was 1.9 (95%CI 1.5, 2.9) per 100 PYO, highest under 5-years old [7.3 (4.8-11.0)], adjusting for dates of birth and study enrollment. Independent risk factors, at enrollment to the cohort, predicting death were low hemoglobin (<5 g/dL) [3.8 (1.8-8.2); p = 0.001] and high total bilirubin (≥102 µmol/L) [1.7 (1.0-2.9); p = 0.044] as determined by logistic regression. CONCLUSIONS: Mortality in SCA in Africa is high, with the most vulnerable period being under 5-years old. This is most likely an underestimate, as this was a hospital cohort and may not have captured SCA individuals with severe disease who died in early childhood, those with mild disease who are undiagnosed or do not utilize services at health facilities. Prompt and effective treatment for anemia in SCA is recommended as it is likely to improve survival. Further research is required to determine the etiology, pathophysiology and the most appropriate strategies for management of anemia in SCA.